Combination Medicaments for Treating Bacterial Infections

ABSTRACT

Use of a monobactam antibiotic of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein the oxyimino group i.e. &gt;C═N—O— has Z-orientation, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a bacterial infection in combination with a carbapenem antibiotic or a pharmaceutically acceptable salt thereof.

The present invention relates to the use of monobactam antibiotic offormula (I) as described herein below and novel pharmaceutical productscomprising a combination comprising said compound and a carbapenemantibiotic.

β-Lactam antibiotics have been widely used for the treatment ofbacterial infections both in hospitals and in the general public. Thereare several classes of β-lactam antibiotics that have found clinicalapplication, these include the penicillins, cephalosporins, cephamycins,carbacephems, oxacephems, carbapenems and monobactams.

The efficiency of all of these classes to cure bacterial infections hasbeen impaired by the appearance of bacteria that are resistant towardsthe antibiotics. The prevalent cause of this resistance in Gram-negativebacteria is the expression by the bacteria of enzymes known asβ-lactamases that are able to hydrolyse the β-lactam antibioticsrendering them inactive. Bacteria are able to produce a variety ofβ-lactamases, including penicillinases, cephalosporinases,cephamycinases, carbapenemases, monobactamases, broad-spectrumβ-lactamases and extended-spectrum β-lactamases.

Monobactam antibiotics (e.g. aztreonam) have been regarded as stabletowards many β-lactamases. Nevertheless there are many strains ofGram-negative bacteria that now exhibit β-lactamase-mediated resistancetowards aztreonam.

Combinations between Aztreonam, i.e.(Z)-2-[[[(2-amino-4-thiazolyl)[[(2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]-carbamoyl]methylene]amino]oxy]-2-methylpropionicacid, and carbapenems (Imipenem or Meropenem) have been investigated asa possible way to overcome bacterial resistance. Although some synergybetween aztreonam and a carbapenem was observed against bacteriabelonging to the Enterobacteriaceae [Sader H S, Huynh H K, Jones R N;Contemporary in vitro synergy rates for aztreonam combined with newerfluoroquinolones and β-lactams tested against Gram-negative bacilli;Diagn. Microbiol. Infect. Dis. 47 (2003) 547-550], the activity of thecombinations against Pseudomonas aeruginosa was devoid of synergy oreven showed antagonism [Sader H S, Huynh H K, Jones R N; Contemporary invitro synergy rates for aztreonam combined with newer fluoroquinolonesand β-lactams tested against Gram-negative bacilli; Diagn. Microbiol.Infect. Dis. 47 (2003) 547-550; Yamaki K, Tanaka T, Takagi K, Ohta M;Effects of aztreonam in combination with antipseudomonal antibioticsagainst Pseudomonas aeruginosa isolated from patients with chronic orrecurrent lower respiratory tract infection. J. Infect. Chemother. 4(1998) 50-55].

WO 98/47895 is directed to 2-oxo-1-azetidine sulfonic acid derivativesof the general formula

wherein the oxyimino fragment

has ‘anti’ orientation as shown in the above formula. ‘anti’ is an olderterm used to designate the trans-isomer of an oxime compound (the prefix‘syn’ was accordingly used to designate the cisof an oxime); cf. IUPACGold Book; IUPAC Compendium of Chemical Terminology, Electronic version,http://goldbook.iupac.org/E0204.html and PAC, 1996, 68, 2193 Basicterminology of stereochemistry (IUPAC Recommendations 1996) on page2207. The disclosed 2-oxo-1-azetidine sulfonic acid derivatives are tobe used in combination with carbapenem antibiotics including Imipenem,Meropenem or Biapenem for the treatment of bacterial infections.R1_(Ref) is preferably a 2-thienyl group and is used in all exemplifiedinventive compounds of said reference. R2_(Ref). can among other groupse.g. be a group of formula:

The ‘anti’ (trans) orientation of the oxyimino fragment is described toprovide excellent synergy with ceftazidime. Example 1 of the referencee.g. refers to(3S)-trans-3-[(E)-2-(2-thienyl)-2-{(1,5-dihydroxy-4-pyridon-2-ylmethoxy)imino}-acetamido]-4-methyl-2-oxazetidine-1-sulfonicacid and is shown to have, together with ceftazidime, antibacterialactivity against numerous strains of pathogenic bacteria.

There is however an increasing formation of resistance towardsconventional monobactam antibiotics, like e.g. Aztreonam. Particularlyin view of this growing resistance, there is an ongoing need for novelalternatives to known monobactam antibiotics as well as for findingnovel antibiotic combinations.

This invention is based on the recent finding of novel monobactamantibiotics and, more particularly, on the novel finding that a specificembodiment of these monobactams, the monobactam antibiotic of formula(I) as described herein below, when used in combination with otherantibiotics, in particular carbapenem antibiotics, shows improvedefficacy against a broad range of bacteria, including Gram-positive andespecially Gram-negative bacteria, including Enterobacte-riaceae andPseudomonas aeruginosa. In particular, the efficacy of the novelcombinations of the monobactam antibiotic of formula (I) with carbapenemantibiotics is for many strains of important pathogenic bacteriasignificantly improved with regard to combinations of Aztreonam with therespective carbapenem antibiotics, e.g. the combinations of Aztreonamwith Meropenem or Imipenem.

Furthermore, the combinations of the present invention frequentlyexhibit a significantly improved efficacy against bacteria when comparedto the best efficacy of the combination partners alone, and frequentlyexhibits a synergistic effect i.e. an effect which is more potent thanwhat one would expect from a purely additive effect.

Thus the present invention relates to the use of the monobactamantibiotic of formula (I)

wherein the oxyimino group, i.e. >C═N—O— is in Z-orientation,(corresponding to the=cis-orientation or syn-orientation in the senseindicated above with regard to WO 98/47895), or a pharmaceuticallyacceptable salt thereof for the manufacture of a medicament for thetreatment of a bacterial infection in combination with one or more thanone carbapenem antibiotic, or pharmaceutically acceptable salts thereof.

In another aspect the invention relates to pharmaceutical productscomprising a monobactam antibiotic of formula (I) as described above ora pharmaceutically acceptable salt thereof and one or more than onecarbapenem antibiotic, or pharmaceutically acceptable salt thereof.

These pharmaceutical products represent improved medicaments for thetreatment of infections caused by pathogenic bacteria, includingGram-positive and particularly Gram-negative bacteria.

Particularly preferred according to the invention is the use of themonobactam antibiotic of formula (I) or a salt thereof for themanufacture of a medicament for the treatment of a bacterial infectionin combination with a single carbapenem antibiotic, or apharmaceutically acceptable salt thereof.

The monobactam antibiotic of formula (I) can e.g. be prepared accordingto the following general Scheme 1:

wherein “HOBT” stands for “hydroxybenzotriazole”, “DCC” for“dicyclohexylcarbodiimide” and “TFA” for “trifluoroacetic acid”. Thereaction of compound of general formula 1a and compound 2 according tosaid scheme is described in Org. Process Res. & Dev. 2002, 863.Alternatively, the coupling reaction of compound of general formula 1awith compound 2 can e.g. be performed with the corresponding acylchloride (Chem. Pharm. Bull. 1983, 2200) or with an activated ester ofcompound 1, such as the N-hydroxysuccinimidyl ester (see Org. ProcessRes. & Dev. 2002, 863), or the benzothiazolyl thioester (see J.Antibiotics 2000, 1071). Alternatively, other coupling reagents, such ashydroxyazabenzotriazole (HOAT),2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate methanaminium (HATU),O-BenzotriazoleN,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU), used for amino acid coupling reactions, can replacehydroxybenzotriazole (HOBT) or benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (PyBOP) (For more detailon suitable coupling reagents, see N. Sewald, H.-D. Jakubke, Peptides:Chemistry and Biology, Wiley-VCH, 2002).

The preparation of compound of general formula 1a can be carried out ina customary way by reacting the appropriate keto acid 1-A3 with theappropriately etherified hydroxylamine 1-A4 as shown in Scheme 2 below:

In the above scheme 2, the preparation of compound 1-A4 from kojic acidand its reaction with compound 1-A3 are described in detail e.g. inEP-A-0 251 299. Compound 1-A3 can be obtained starting from compound1-A0 as shown in the upper part of above scheme 2. The compounds 1-A0can be prepared according to known methods and are partiallycommercially available, e.g. ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate(R in formula 1-A0=ethyl) from CHEMOS GmbH, 93128 Regenstauf, Germany).The oxidation of 1-A0 to 1-A2 with e.g. selenium dioxide may beperformed in analogy to the oxidation described in the second step ofexample 1 of GB-A-1 575 804.

Compound 2 of Scheme 1 can e.g. be manufactured according to the routein Scheme 3:

wherein “DMF SO₃” stands for the dimethylformamide-sulphur trioxidecomplex and “TFA” for trifluoroacetic acid. In the above scheme 3,starting material 2-A3 can be prepared as described on page 2790 ofTetrahedron Lett. 1986, p. 2789-2792 (a direct synthesis for theoptically active (S)—N-Boc-3-hydroxyvaline, required in turn there asthe starting material, can be found in the last example of J. Org. Chem.2003, 68, p. 177-179). The conversions from 2-A3 to 2-A4, to 2-A5 and to2 are described in more detail e.g. in the examples of J. Antibiotics,1985, p. 1536-1549 (see Scheme 1 of said reference).

In scheme 1 above

R^(A) represents an amine protecting group such as formyl,trifluoroacetyl, O-nitrophenoxyacetyl, chloroacetyl, trichloroacetyl,y-chlorobutyryl, benzyloxycarbonyl, pchlorobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, pbromobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl,ter-butyloxycarbonyl, isopropyloxycarbonyl, diphenylmethyl,triphenylmethyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl; and

R^(B) and R^(C) represent independently of one another an alcoholprotecting group such as benzyloxycarbonyl, pchlorobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, pbromobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl,ter-butyloxycarbonyl, isopropyloxycarbonyl, diphenylmethyl,triphenylmethyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl,trialkylsilane such as trimethylsilane, triethylsilane orter-butyldimethylsilane.

Said amine and alcohol protecting groups can be easily removed, e.g. byacid hydrolysis or other well known techniques. [for more detail seee.g. T. W. Greene et al. Protective Groups in Organic Chemistry, Wileyintersience, 1999]. The protecting groups in compounds of generalformula 1a can easily be introduced by well known synthetic methods.[for more detail see e.g. T. W. Greene et al. Protective Groups inOrganic Chemistry, Wiley intersience, 1999].

The deprotection of functional groups may be carried out either byhydrogenation or hydrolysis with appropriate acids, such as hydrochloricacid, formic acid, acetic acid, trifluoroacetic acid, phosphoric acid,NaH PO₄, Na HPO₄, ptoluenesulfonic acid or methanesulfonic acid, insolvents such as methanol, ethanol, propanol, ethyl acetate,acetonitrile, methylene chloride or ethylene chloride. The hydrogenationis usually carried out in the presence of a metal catalyst, such as Pd,Pt or Rh under normal to high pressure. The deprotection of thedifferent functional groups can be carried out either simultaneously orsequentially.

The solvents of choice for the reaction are selected based upon thereactants used and from solvents such as benzene, toluene, acetonitrile,tetrahydrofurane, ethanol, methanol, chloroform, ethyl acetate,methylene chloride, dimethyl formamide, dimethyl sulfoxide, hexamethylphosphoric triamide or the like. Solvents mixtures may also be used.

Reaction temperatures would generally range from between −70° C. to 150°C. The preferred molar ratio of the reactants is 1:1 to 1:5. Thereaction time range from 0.5 to 72 hours, depending on the reactants.

Examples of pharmaceutically acceptable salts of the compound of formula(I) include e.g. salts of inorganic base like ammonium salts, alkalimetal salts, in particular sodium or potassium salts, alkaline earthmetal salts, in particular magnesium or calcium salts; salts of organicbases, in particular salts derived from cyclohexylamine, benzylamine,octylamine, ethanolamine, diethylolamine, diethylamine, triethylamine,ethylendiamine, procaine, morpholine, pyrroline, piperidine,N-ethylpiperidine, N-methylmorpholine, piperazine as the organic base;or salts with basic amino acids, e.g. lysine, arginine, ornithine,histidine and the like.

Such salts can be manufactured in a way known per se, e.g. by reactingthe compound of formula (I) with an appropriate base, preferably at roomtemperature or below, e.g. from about 2° C. to about 25° C. andisolating the salt formed, e.g. by lyophilization.

The compounds of formula (I) are optionally used in substantiallycrystalline form. A substantially crystalline compound of formula (I)has not yet been described before. It can be obtained by crystallisationmethods, e.g. as described in the Examples of the present application.For the purposes of this application the term “substantiallycrystalline” means that an X-Ray Powder Diffraction (XRPD) diagram of acorresponding substance shows one or more distinct peaks which have amaximum height corresponding to at least the fivefold of their width athalf-maximum. Generally, the degree of crystallinity of a substanceincreases with an increasing average value for the ratio of the heightof a certain peak to its width at half-maximum. Furthermore, the XRPDdiagram shall show a substantially constant base line (baseline=a lineconnecting the minima of the XRPD diagram curve) over the entire scanned2-theta range, indicating the substantial absence of amorphous material.in the recorded sample. “Substantially constant base line” means for thepurposes of this application that the baseline does preferably not risefor more than the height of the lowest peak of said diagram.

A further subject of the present invention is therefore the compound offormula (I) being in substantially crystalline form.

Said substantially crystalline compound of formula (I) shows peaks inthe X-Ray Powder Diffractogram (XRPD) having a relative Intensity ofmore than 50%, recorded with Cu K-alpha Radiation and given in[°2-Theta], at about 6.8±0.1, 15.1±0.1, 15.6±0.1 and 25.4±0.1, andexhibits a X-Ray Powder Diffraction pattern, recorded with Cu K-alpharadiation, essentially as follows:

2Θ [° ± 0.1°] Rel Int 6.86 m 13.32 w 13.72 w 15.11 st 15.57 vst 22.84 w25.37 m 26.32 w 27.08 w 28.38 w 28.74 w

wherein

vst stands for a relative intensity of 100% to 90%; st stands for arelative intensity of less than 90% to 65%; m stands for a relativeintensity of less than 65% to 50%; and

w stands for a relative intensity of less than 50% to 30%, morespecifically the following X-Ray Powder Diffraction pattern recordedwith Cu K-alpha radiation and indicating the diffraction peaks with arelative Intensity of 20% and more:

2Θ [° ± 0.1°] Rel Int ** 6.86  64 ± 13 13.32 27 ± 6 13.72 28 ± 6 15.11 69 ± 14 15.57 100 ± 20 17.41 29 ± 6 17.88 20 ± 4 22.84 31 ± 6 24.49 22± 4 25.37  52 ± 10 26.32 36 ± 7 27.08 34 ± 7 28.38 33 ± 7 28.74 32 ± 631.00 23 ± 5 ** with typical variation of the indicated values for therelative intensity

It is known that the values for the relative Intensity of the peaks aremore strongly dependent from certain properties of the measured samplethan the line position, e.g. from the size of the crystals and/or theirorientation in the sample. Variations of about ±20% of the shown peakintensities are therefore likely to occur.

FIG. 1 shows the XRPD diagram of typical crystalline material of thecompound of formula (I) recorded with Cu K-alpha radiation.

The compound of formula (I) and its pharmaceutically compatible saltsare used according to the invention in combination with otherantibiotics like in particular carbapenem antibiotics orpharmaceutically acceptable salts thereof as antibiotically effectivemedicaments in the control or prevention of infectious diseases inmammals, human and non-human, in particular bacterial infections, moreparticularly infections in which Gram-positive bacteria and mostlypreferred in which Gram-negative bacteria are involved, such as e.g.nosocomial pneumonia, community-acquired pneumonia, urinary tractinfection, complicated intra-abdominal infection, complicated skin/skinstructure infection, infectious exacerbations of cystic fibrosis,sepsis, melioidosis.

In this sense, the compound of formula (I) and its pharmaceuticallyacceptable salts are used according to the invention in combination witha carbapenem antibiotic or pharmaceutically acceptable salt thereof forsuch treatment. Although not preferred, there may be certain situations,wherein the use of compound (I) or a salt thereof with two or even moredifferent carbapenem antibiotics may be of advantage and indicated.

For the purposes of this application, the term “carbapenem antibiotic”refers to antibiotically effective compounds comprising the structuralelement:

Numerous carbapenem antibiotics are known in the art, and can, ingeneral, be used for the purposes of the present invention. Suitableexamples are described e.g. in A. BRYSKIER “Carbapenems”, ANTIMICROBIALAGENTS: ANTIBACTERIALS AND ANTIFUNGALS, page 270-321, Publisher:American Society for Microbiology, Washington D.C., 2005, and referencescited therein. The term “carbapenem antibiotic” includes inner saltslike e.g. ME 1036 or Biapenem.

In addition to the mentioned inner salts other pharmaceuticallyacceptable salts of carbapenem antibiotics may also be used for thepurposes of the present invention, e.g. acid addition salts derived frompharmaceutically acceptable organic and/or inorganic acids.

Preferably, the carbapenem antibiotics used according to the presentinvention, are compounds of formula (II), or pharmaceutically acceptablesalt thereof:

wherein

R¹ represents hydrogen or C₁-C₆alkyl;

R² represents hydrogen or C₁-C₆alkyl;

R³ represents hydrogen, C₁-C₆alkyl, C₁-C₆alkoxy; —(C_(1n)H_(2n))—R⁵ or—O—(C_(1n)H_(2n))—R⁵;

wherein

R⁵ represents halogen, cyano, C₁-C₆alkoxy, amino, (C₁-C₆alkyl)amino,di(C₁-C₆alkyl)amino, or a group of formula —CO—R⁶, —NH—CO—R⁶—CO—NH₂,—NH—CO—NH₂, —NH—SO₂—NH₂ or —NH—(C═NH)—NH₂, in which groups one or moreof the hydrogen atoms may also be replaced with R⁶ or the —NH₂ residueof the group can be replaced with a 5-6 membered heterocyclic ring boundto the group via a nitrogen atom present in the ring which heterocyclicring may be unsubstituted or substituted with one or more of asubstituent S², wherein each S² has independently of other substituentsS² one of the meanings defined below; and

R⁶ represents C₁-C₆alkyl, phenyl or a 5-6 membered heterocyclic ring andmay be unsubstituted or substituted with one or more of a substituentS¹, wherein each S¹ has independently of other substituents S¹ one ofthe meanings defined below; and

n is an integer from 1 to 6;

R⁴ represents a group of formula —(S)_(m)—R⁷, wherein

m is 0 or 1 and

R⁷ represents hydrogen; C₁-C₆alkyl, unsubstituted or substituted withone or more of a substituent S¹; phenyl, unsubstituted or substitutedwith one or more of a substituent S¹; or a 3-6 membered heterocyclylgroup containing one or more than one heteroatom selected from nitrogen,sulfur and oxygen, which heterocyclyl group may furthermore optionallybe fused to a phenyl ring or a 5-6 membered heterocyclic ring and whichwhole group is unsubstituted or substituted with one or more of asubstituent S¹; wherein each

S¹ is independently of other substituents S¹ selected C₁-C₆alkyl,unsubstituted or substituted with one or more of a substituent S²;phenyl, unsubstituted or substituted with one or more of a substituentS²; or a 3-6 membered heterocyclyl group containing one or more than oneheteroatom selected from nitrogen, sulfur and oxygen, which heterocyclylgroup may furthermore optionally be fused to a phenyl ring or a 5-6membered heterocyclic ring and which whole group is unsubstituted orsubstituted with one or more of a substituent S²; C₁-C₆alkoxy, hydroxyl,carboxy, amino, C₁-C₆alkyl amino, di(C₁-C₆)alkyl amino, cyano, halogen,or a group of formula CO—R⁸, —NH—CO—NH₂, —CO—NH₂, —NH—CH═NH,—(C═NH)—C₁-C₆alkyl, —NH—CO—NH₂, —NH—SO₂—NH₂ or —NH— (C═NH)—NH₂, in whichgroups one or more of the hydrogen atoms may also be replaced with R⁸ orthe —NH₂ residue of the group can be replaced with a 5-6 memtieredheterocyclic ring bound to the group via a nitrogen atom present in thering which heterocyclic ring may be un-substituted or substituted withone or more of a substituent S², wherein each S² has independently ofother substituents S² one of the meanings defined below; and

R⁸ represents C₁-C₆alkyl, unsubstituted or substituted with one or moreof a substituent S²; phenyl, unsubstituted or substituted with one ormore of a substituent S²; or a 3-6 membered heterocyclyl groupcontaining one or more than one heteroatom selected from nitrogen,sulfur and oxygen, which heterocyclyl group may furthermore optionallybe fused to a phenyl ring or a 5-6 membered heterocyclic ring and whichwhole group is unsubstituted or substituted with one or more of asubstituent S², wherein each

S² is independently from other substituents S² selected from C₁-C₆alkyl,unsubstituted or substituted with one or more of a substituent S³;phenyl, unsubstituted or substituted with one or more of a substituentS³; or a 3-6 membered heterocyclyl group containing one or more than oneheteroatom selected from nitrogen, sulfur and oxygen, which heterocyclylgroup may furthermore optionally be fused to a phenyl ring or a 5-6membered heterocyclic ring and which whole group is un-substituted orsubstituted with one or more of a substituent S³; C₁-C₆alkoxy, hydroxyl,carboxy, amino, C₁-C₆alkyl amino, di(C₁-C₆)alkyl amino, cyano, halogen,or a group of formula —CO—R⁹, —NH—CO—R⁹; —CO—NH₂, —NH—CH═NH, —NH—CO—NH₂,—NH—SO₂—NH₂ or —NH—(C═NH)—NH₂, in which groups one or more of thehydrogen atoms may also be replaced with R⁹ or the —NH₂ residue of thegroup can be replaced with a 5-6 membered heterocyclic ring bound to thegroup via a nitrogen atom present in the ring which heterocyclic ringmay be unsubstituted or substituted with one or more of a substituentS³, wherein each S³ has independently of other substituents S³ one ofthe meanings defined below; and

R⁹ represents C₁-C₆alkyl, unsubstituted or substituted with one or moreof a substituent S³; phenyl, unsubstituted or substituted with one ormore of a substituent S³; or a 3-6 membered heterocyclyl groupcontaining one or more than one heteroatom selected from nitrogen,sulfur and oxygen, which heterocyclyl group may furthermore optionallybe fused to a phenyl ring or a 5-6 membered heterocyclic ring and whichwhole group is unsubstituted or substituted with one or more of asubstituent S³, wherein each

S³ independently of other substituents S³ represents unsubstitutedC₁-C₆alkyl, unsubstituted phenyl or an unsubstituted 5-6 memberedheterocyclic ring; C₁-C₆alkoxy, hydroxyl, carboxy, amino, C₁-C₆alkylamino, di(C₁-C₆)alkyl amino, cyano, halogen, or a group of formula—NH—CO—NH₂, —CO—NH₂, —NH—CH═NH, —NH—CO—NH₂, —NH—SO₂—NH₂ or —NH—(C═NH)—NH₂; or R³ and R⁴ together form a C₃-C₇polymethylene group, whichis unsubstituted or substituted with one or more of a substituent S³,wherein each S³ has independently of other substituents S³ one of themeanings defined above.

The term “C₁-C₆alkyl” and “—(C_(1n)H_(2n))—”, as used in the presentapplication, refers to branched or, preferably, straightchain C₁-C₆alkylor —(C_(1n)H_(2n))—, wherein n is an integer from 1 to 6, preferablyfrom 1 to 4, such as in particular methyl, ethyl, propyl, butyl, pentyl,hexyl, isopropyl, isobutyl, tert-butyl or neopentyl. Preferred areC₁-C₄alkyl groups. The term “C₁-C₆alkoxy” means an alkoxy group based ona C₁-C₆alkyl according to the above definition.

The term “C₃-C₇polymethylene group” refers to a group of formula—(CH₂)₃₋₇— which may comprise one or two double bonds and which may beunsubstituted or substituted as specified.

The terms “heterocyclyl group” and “heterocyclic ring” refer tocorresponding groups which are saturated or unsaturated.

The term “a 3-6 membered heterocyclyl group containing one or more thanone heteroatom selected from nitrogen, sulfur and oxygen, whichheterocyclyl group may furthermore optionally be fused to a phenyl ringor a 5-6 membered heterocyclic ring” refers e.g. to azetidin, thiophen,benzothiophen, furan, pyran, benzofuran, isobenzofuran, pyrrol,imidazole, pyrazole, pyridin, pyrazin, pyrimidin, pyridazin, indazolin,indol, isoindol, indazol, purin, oxazol, isooxazol, furazan, pyrrolidin,pyrrolin, imidazolidin, piperidin, piperazin, thiazol, isothiazol,thiazepine or hydrothiazepin. Many other suitable heterocyclic groupsfor the purposes of the invention are known to the skilled personsand/or can be readily found in the literature. Preferred are 5-6membered heterocyclic groups containing one or more than one heteroatomselected from nitrogen, sulfur and oxygen, in particular nitrogen andsulphur, which heterocyclyl group may furthermore optionally be fused toa phenyl ring or a 5-6 membered heterocyclic ring containing one or morethan one heteroatom selected from nitrogen, sulfur and oxygen, inparticular nitrogen and sulphur.

“Substituted by one or more than one” means preferably “substituted byone or two”, e.g. “substituted by one”.

More preferably R⁵ represents halogen, cyano, C₁-C₆alkoxy, amino,(C₁-C₆alkyl)amino, di(C₁-C₆alkyl)amino, or a group of formula —CO—R⁶,—NH—CO—R⁶—CO—NH₂, —NH—CO—NH₂, —NH—SO₂—NH₂ or —NH—(C═NH)—NH₂, wherein R⁶represents C₁-C₆alkyl, phenyl or a 5-6 membered heterocyclic ring andmay be unsubstituted or substituted with one or more of a substituentselected from one of the substituents S³ as defined above.

The term halogen refers to fluorine, chlorine, bromine and iodine,preferably fluorine and chlorine.

Another group of particularly preferred compounds of formula (II) arethe compounds, wherein R⁴ represents a group of formula —(S)_(m)—R⁷, mis 0 or 1 and R⁷ represents a 3-6 membered heterocyclic group containingone or more than one heteroatom selected from nitrogen, sulfur andoxygen, which heterocyclyl group may furthermore optionally be fused toa phenyl ring or a 5-6 membered heterocyclic ring and which whole groupis un-substituted or substituted as defined in detail above. Even morepreferred are such compounds of formula (II), when m is 1.

Also preferred are the compounds of formula (II), wherein

R¹ represents hydrogen or C₁-C₆alkyl;

R² represents hydrogen or C₁-C₆alkyl; and

R³ represents C₁-C₆alkyl;

in particular, when one of R¹ and R² represents hydrogen and the other—CH₃ and R³ is —CH₃.

The compounds of formula (III),

wherein

Y represents nitrogen or >CH—;

S⁴ represents hydrogen or has the meaning of S¹ as defined above; and

R represents hydrogen; C₁-C₄alkyl, in particular methyl, or—(N═H)—C₁-C₄alkyl, in particular —(N═H)—CH₃, or

S⁴ and R together the nitrogen atom or group Y to which they are boundform a 5-6 membered heterocyclic ring;

R being most preferably hydrogen or methyl,

or pharmaceutically acceptable salts thereof,

form another group of embodiments of a carbapenem which is particularlypreferred for the purposes of the present invention.

The following carbapenem antibiotics or their pharmaceuticallyacceptable salts are specifically preferred examples useful in thepresent invention:

In medicinal practice Panipenem is generally used together withBetamipron, a renal inhibitor which inhibits renal uptake of Panipenemas known in the art.

Particularly preferred carbapenem antibiotics for use in the presentinvention are selected from the following compounds:

or a pharmaceutically acceptable salt thereof.

A further preferred subject of the present invention is the use of themonobactam antibiotic of formula (I) as described above or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of a bacterial infection in combinationwith Imipenem or a pharmaceutically acceptable salt thereof. Inmedicinal practice Imipenem is generally used together with Cilastin, aninhibitor of the renal dipeptidase in the proximal tubulus of thekidney, which is used in order to stabilize Imipenem againstinactivation, similar as the Betamipron in combination with Panipenem asmentioned above.

Another preferred subject of the present invention is use of themonobactam antibiotic of formula (I) as described above or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of a bacterial infection in combinationwith Meropenem or a pharmaceutically acceptable salt thereof. Meropenemis sometimes also used together with Cilastin similar to Imipenem(Antimicrob. Agents Chemother. 2000, 44, 885-890).

Another preferred subject of the present invention is use of themonobactam antibiotic of formula (I) as described above or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of a bacterial infection in combinationwith Ertapenem or a pharmaceutically acceptable salt thereof.

Yet another preferred subject of the present invention is use of themonobactam antibiotic of formula (I) as described above or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of a bacterial infection in combinationwith Doripenem or a pharmaceutically acceptable salt thereof.

The compound of formula (I) or the pharmaceutically acceptable saltsthereof can be administered according to the invention before,simultaneously with or after the administration of the carbapenemantibiotic or the pharmaceutically acceptable salt thereof.Substantially simultaneous or an exactly simultaneous administration ofthe combination partners is generally preferred.

The compounds of formula (I) or pharmaceutically acceptable saltsthereof and the carbapenem antibiotics or pharmaceutically acceptablesalts thereof can be administered by any route of administration,preferably in the form of a pharmaceutical composition adapted to suchroute. Dosage and route of administration should be determined bysusceptibility of the causative organisms, severity and site ofinfection, and the specific condition of the patient and be selectedaccordingly. Preferred types of pharmaceutical compositions are, forexample, administered orally, by inhalation or more preferablyparenterally e.g. intravenously or intramuscularly.

Formulations for parenteral administration include but are not limitedto the form of aqueous isotonic sterile injections, solutions,concentrates or solutions for further dilutions (e.g. for infusions), orsuspensions, including nanosuspensions and nanocrystals. These solutionsor suspensions can be prepared from sterile powders, granules orlyophilizates. The compounds can be dissolved in sterile water or invarious sterile buffers that may contain, but are not limited tocontain, sodium chloride, polyethylene glycol, propylene glycol,ethanol, sucrose, glucose, arginine, lysine, citric acid, lactic acidphosphoric acid and corresponding salts. The formulation can containfrom 0.1% to 99% by weight, preferably 10%-90% by weight, of each of theactive ingredients. If the compositions contain dosage units, each unitpreferably contains from 50 mg to 4 g of each active substance.

A further subject of the present invention is accordingly apharmaceutical product comprising the compound of formula (I) or apharmaceutically acceptable salt thereof and a carbapenem antibiotic ora pharmaceutically acceptable salt thereof.

A pharmaceutical product according to the invention can e.g. compriseone or more than one dosage unit of a compound of formula (I) or apharmaceutically acceptable salt thereof and one or more than one otherdosage unit containing a carbapenem antibiotic or a pharmaceuticallyacceptable salt thereof and being free of the compound of formula (I).By the way of example, a pharmaceutical product of the invention maycomprise two separate packages, each of them comprising a pharmaceuticalformulation comprising just one of the combination partners in anappropriate dosage form.

Another embodiment of the pharmaceutical product according to theinvention comprises one or more than one dosage unit, and each dosageunit comprises both, the compound of formula (I) or a pharmaceuticallyacceptable salt thereof and a carbapenem antibiotic or apharmaceutically acceptable salt thereof. Such a fixed dose combinationgenerally comprises the compound of formula (I) or the pharmaceuticallyacceptable salt thereof and the carbapenem antibiotic or thepharmaceutically acceptable salt thereof as well as a pharmaceuticallyacceptable carrier and optionally appropriate further excipients astypical for the respective dosage form.

The pharmaceutical products according to the present invention comprisethe compound of formula (I) or the pharmaceutically acceptable saltthereof and the carbapenem antibiotic or the pharmaceutically acceptablesalt thereof in an appropriate weight ratio, e.g. in a weight ratio of10:1 to 1:10, preferably from 5:1 to 1:5, more preferably from 3:1 to1:3 like e.g. from 2:1 to 1:2 or about 1:1.

The pharmaceutical products according to the present invention areactive against a variety of bacterial organisms, in particular againstGram-positive bacteria including for example Staphylococcus aureus,Staphylococccus epidermidis, Enterococcus faecalis, Streptococcuspneumonia and Gram-negative bacteria, including Enterobacteriaceae, forexample Escherichia coli, Enterobacter cloacae, Enterobacter aerogenes,Citrobacter freundii, Klebsiella pneumoniae, Klebsiella oxytoca, Proteusvulgaris, Providencia rettgeri; Pseudomonas for example P. aeruginosa;Acinetobacter for example A. baumannii; Burkholderia, for example B.cepacea; B. mallei; B. pseudomallei; Stenotrophomonas for example S.maltophilia; Haemophilus influenzae.

The products can thus be used for treatment of infectious diseasesincluding e.g. nosocomial pneumonia, community-acquired pneumonia,urinary tract infection, complicated intra-abdominal infection,complicated skin/skin structure infection, cystic fibrosis, sepsis.

The dosage of the compound of formula I and of the pharmaceuticallycompatible salts thereof and the carbapenem antibiotics or salts thereoffor said treatment can vary within wide limits and will be fitted ineach particular case to the individual requirements of the patient to betreated and to the pathogens to be controlled. In general, a dosage ofabout 0.1 to about 4 g, e.g. about 0.5 to about 2 g, of total antibioticadministered one to four times over a 24 hours period should beappropriate.

The present invention is further illustrated by the followingnon-limiting examples.

EXAMPLE 1 Preparation of(3S)-3-{(2Z)-2-(2-amino(1,3-thiazol-4-yl))-3-[(1,5-dihydroxy-4-oxo(2-hydropyridyl))methoxy]-3-azaprop-2-enoylamino}-4,4-dimethyl-2-oxoazetidinylhydroxysulfonate (Compound of Formula (I))

The monobactam antibiotic I is prepared according to the synthesisoutlined in Scheme 4 and according to the procedures described below.

Preparation of(3S)-3-{(2Z)-3-{[1,5-bis(diphenylmethoxy)-4-oxo(2-hydropyridyl)]methoxy}-2-{2-[(triphenylmethyl)amino](1,3-thiazol-4-yl)}-3-azaprop-2-enoylamino}-4,4-dimethyl-2-oxoazetidinylhydroxysulfonate (3)

Using HOBt as coupling reagent(2Z)-3-{[1,5-Bis(diphenylmethoxy)-4-oxo(2-hydropyridyl)]-methoxy}-2-{2-[(triphenylmethyl)amino](1,3-thiazol-4-yl)}-3-azaprop-2-enoicacid 1 (0.89 g, 0.95 mmol, J. Antibiotics 1990, 1450 and WO-A-02/22613),hydroxybenzotriazol (HOBT) (0.14 g, 1.03 mmol) anddicyclohexylcarbodiimide (0.26 g, 1.41 mmol) are dissolved in DMF (25mL) at room temperature. First,(3S)-3-Amino-4,4-dimethyl-2-oxoazetidinyl hydroxysulfonate 2 (0.20 g,0.95 mmol, J. Org. Chem. 2003, 177 and Tetrahedron Lett. 1986, 2786) andthen 30 min later NaHCO₃ (0.09 g, 1.05 mmol) are added to the previoussolution. The resulting mixture is stirred for 18 h. The precipitateformed is filtrated and ethyl acetate is added to the filtrate. Theorganic phase is washed twice with an aqueous solution saturated withNaCl, dried over Na SO₄ and the solvents are evaporated in vacuo. Theresidue is triturated in ethyl acetate (30 mL) to afford 0.5 g of thedesired compound 3 as white solid after filtration.

HPLC purity: 98%.

Using HATU as Coupling Reagent

A solution of DMSO (10 mL) containing HATU (1.38 g, 3.64 mmol) is addedat room temperature to a suspension of(2Z)-3-{[1,5-Bis(diphenylmethoxy)-4-oxo(2-hydropyridyl)]methoxy}-2-{2-[(triphenylmethyl)amino](1,3-thiazol-4-yl)}-3-azaprop-2-enoicacid 1 (3.0 g, 3.16 mmol, J. Antibiotics 1990, 1450 and WO-A-02/22613)and (3S)-3-mino-4,4-dimethyl-2-oxoazetidinyl hydroxysulfonate 2 (1.18 g,5.06 mmol, J. Org. Chem. 2003, 177 and Tetrahedron Lett. 1986, 2786) inDMSO (20 mL). Then NaHCO₃ (0.81 g, 9.65 mmol) is added as solid. Theresulting mixture, which becomes a solution after 1 h, is stirred for 24h at room temperature. Ethyl acetate (50 mL) is then added and theresulting solution is washed 6 times with brine (6×30 mL). The organicphase dried over Na SO₄ and the mixture is concentrated by evaporationof the solvent in vacuo until about 25 mL of solution remain in theflask. At room temperature, cyclohexane (40 mL) is added dropwise to theyellow solution. The resulting precipitate is collected by filtrationand the cake is then washed with cyclohexane (2×5 mL) to give 3.3 g ofthe desired compound 3.

HPLC purity: 95%.

Both methods give a product with the same NMRand MS spectra.

¹H-NMR (DMSO-d₆) δ: 1.05 (s, 3H), 1.34 (s, 3H), 4.49 (d, 1H, J=7.8 Hz),4.62 (m, 2H), 6.12 (s, 1H), 6.33 (s, 1H), 6.39 (s, 1H), 6.72 (s, 1H),7.20-7.43 (m, 35H), 7.72 (s, 1H), 8.83 (1, 1H), 9.52 (d, 1H, J=7.8 Hz).

Preparation of(3S)-3-{(2Z)-2-(2-amino(1,3-thiazol-4-yl))-3-[(1,5-dihydroxy-4-oxo(2-hydropyridyl))methoxy]-3-azaprop-2-enoylamino}-4,4-dimethyl-2-oxoazetidinylhydroxysulfonate (I) (a) Using Trifluoroacetic Acid

(3S)-3-{(2Z)-3-{[1,5-Bis(diphenylmethoxy)-4-oxo(2-hydropyridyl)]methoxy}-2-{2-[(triphenylmethyl)amino](1,3-thiazol-4-yl)}-3-azaprop-2-enoylamino}-4,4-dimethyl-2-oxoazetidinylhydroxysulfonate 3 (0.25 g, 0.23 mmol) and triethylsilane (0.08 g, 0.69mmol) are dissolved in dichloromethane (15 mL) and cooled at −10° C.Then trifluoroacetic acid (1.04 g, 9.2 mmol) is slowly added to thecooled mixture. The temperature is slowly raised to 25° C. and thereaction is stirred for an additional 4 h. The solvent is removed invacuo and the residue was triturated with a solvent mixture containinghexane and ethyl acetate (1:4) to give 0.11 g of the desired compound Ias a solid.

HPLC purity: 94%.

(b) Using Formic Acid

In formic acid (3 mL) at 5° C.,(3S)-3-{(2Z)-3-{[1,5-Bis(diphenylmethoxy)-4-oxo(2-hydropyridyl)]methoxy}-2-{2-[(triphenylmethyl)amino](1,3-thiazol-4-yl)}-3-azaprop-2-enoylamino}-4,4-dimethyl-2-oxoazetidinylhydroxysulfonate 3 (0.40 g, 0.31 mmol) is added and the clear solutionis stirred for 5 h at 5-10° C. Then ethyl acetate (40 mL) is added andthe resulting precipitate is filtrated off. The white precipitate iswashed with additional ethyl acetate (2×5 mL) and give after dryingunder vacuum 0.09 g of the desired compound I

HPLC purity: 92%.

Both methods give a product with the same NMR and MS spectra.

¹H-NMR (DMSO-d₆) δ: 1.22 (s, 3H), 1.42 (s, 3H), 4.63 (d, 1H, J=7.7 Hz),5.28 (s, 2H), 6.81 (s, 1H), 7.13 (s, 1H), 7.27 (br s, 2H), 8.19 (s, 1H),9.59 (d, 1H, J=7.7 Hz).

-ESI-MS spectrum: m/z: 517 [M-H]⁺.

According to the methods described above, the compound of formula (I) isgenerally obtained in an amorphous form. Although it may be used in saidform it may optionally be converted into crystalline material, e.g. asdescribed herein below.

Crystallisation Procedure for Compound of Formula I

The crude material of compound of formula I previously prepared (1.31 g)is suspended in acetonitrile (15 mL) at room temperature. Then water(3.30 mL) is added to the previous suspension. The clear solution (ifsolution is not clear, the suspension could be gently warmed) is stirredat room temperature for a few minutes until the crystallisation started.The suspension is stirred for 1 h at room temperature and an additionalhour at 0° C. After filtration, 1.05 g of compound of formula I isobtained as white crystalline material, which has the same NMR and MSspectra as reported previously for amorphous material.

The crystalline material is characterized by an infrared spectrum aslisted in the following table (FTIR recorded with powder at a resolutionof 2 cm⁻¹, collecting 16 scans from 4000 to 500 cm⁻¹, Bruker Vector 22spectrometer with ATR Golden gate).

FTIR spectrum of crystalline material of the compound of formula (I):

Wavenumber (cm⁻¹) 3102.51 2739.68 1766.15 1634.10 1587.99 1527.491449.58 1357.88 1335.03 1286.46 1239.18 1204.65 1165.49 1129.59 1044.691021.99 1010.65 941.13 907.87 861.18 823.99 802.53 712.18 678.48 628.91583.63 569.68 550.26 536.37 525.52 515.44

The crystalline material exhibits an X-Ray Power Diffraction (“XRPD”)pattern obtained using CuKa radiation as shown in the following Tableand in FIG. 1.

XRPD Diagram 2θ angle (°) Rel. Intensity % 6.86 64 7.19 3 10.73 7 10.975 13.32 27 13.72 28 15.11 69 15.57 100 17.41 29 17.68 13 17.88 20 18.7815 18.95 14 19.34 16 19.76 4 20.38 8 20.66 16 20.86 15 21.55 3 22.27 1022.84 31 23.45 18 23.62 19 23.97 16 24.49 22 24.87 16 25.37 52 26.32 3627.08 34 27.74 12 28.38 33 28.74 32 29.17 11 29.97 10 30.53 12 31.00 2332.47 2 33.27 17 34.47 5 36.12 3 37.04 9 37.44 6 37.98 12 38.19 12 38.689 39.30 5 39.75 7

The 2θ angles have an error of about ±0.1°. It is known that the valuesfor the relative Intensity of the peaks are more strongly dependent fromcertain properties of the measured sample than the line position, e.g.from the size of the crystals and their orientation in the sample.Variations of ±20% of the shown peak intensities are therefore likely tooccur.

The crystalline material is furthermore characterized by ThermalGravimetric Analysis (“TGA”) data as indicated in the Table below andobtained using a scan rate of 10 deg/min (Perkin-Elmer TGS2). The weightloss of the material is about 7% when the temperature of the material israised from room temperature to 100° C. A further weight loss isobserved at 192-193° C. corresponding to the melting/decompositiontemperature of the sample.

Temperature [° C.] Weight loss [%] 25 1.12 50 4.46 75 5.70 100 8.05 1258.09 150 8.14 175 8.29 200 55.60 225 56.10 250 56.31 275 56.52 300 56.75325 57.06 350 57.55 375 58.35 400 29.54 425 60.99 450 62.51 475 63.95500 65.30

EXAMPLE 2 (a) Preparation of the Sodium Salt of Compound of Formula I

Sodium hydrogen carbonate (0.0077 g, 0.095 mmol) is added portionwise toa water solution (20 mL) cooled at 5° C. containing compound of formulaI (0.05 g, 0.1 mmol) (pH 2-3). The clear solution is stirred for 15minutes at 5° C. (pH 5-6). The solution is frozen and lyophilized overthe night to give 0.052 g of a white solid.

¹H-NMR (DMSO-d₆) δ: 1.24 (s, 3H), 1.45 (s, 3H), 4.65 (d, 1H, J=7.7 Hz),5.20 (s, 2H), 6.82 (s, 1H), 6.90 (s, 1H), 7.26 (br s, 2H), 7.95 (s, 1H),9.60 (d, 1H, J=7.7 Hz).

(b) Preparation of the L-Arginine Salt of Compound of Formula I

Compound of formula I (0.20 g, 0.39 mmol) and L-arginine (0.0672 g, 0.39mmol) are vigorously mixed as solid together at room temperature. Theresulting powder is dissolved in water (40 mL) and stirred for 2-3 minat room temperature. The solution is frozen and lyophilized over thenight to give 0.260 g of a white solid.

¹H-NMR (DMSO-d₆) δ: 1.24 (s, 3H), 1.44 (s, 3H), 1.50-1.80 (m, 4H), 3.11(br m, 2H), 3.53 (br m, 1H), 4.65 (d, 1H, J=7.7 Hz), 5.10 (s, 2H), 6.72(s, 1H), 6.80 (s, 1H), 7.22 (br s, 2H), 7.72 (s, 1H), 8.13 (br s, 1H),9.60 (d, 1H, J=7.7 Hz).

(c) Preparation of the L-Lysine Salt of Compound of Formula I

Compound of formula I (0.20 g, 0.39 mmol) and L-lysine (0.0564 g, 0.39mmol) are vigorously mixed as solid together at room temperature. Theresulting powder is dissolved in water (45 mL) and stirred for 2-3 minat room temperature. The solution is frozen and lyophilized over thenight to give 0.250 g of a white solid.

¹H-NMR (DMSO-d₆) δ: 1.24 (s, 3H), 1.30-1.80 (m, 9H), 2.77 (br m, 2H),3.50 (br m, 1H), 4.66 (d, 1H, J=7.7 Hz), 5.11 (s, 2H), 6.73 (s, 1H),6.79 (s, 1H), 7.22 (br s, 2H), 7.73 (s, 1H), 9.61 (d, 1H, J=7.7 Hz).

EXAMPLE 3

Antimicrobial activity of the compounds and of their combinations isdetermined against a selection of organisms according to standardprocedures described by the National Committee for Clinical LaboratoryStandards (NCCLS document M7-A6). The compounds are dissolved in 100%DMSO or sterile broth according to their aqueous solubility and arediluted to the final reaction concentration (0.06-32 μg/mL) in microbialgrowth media (IsoSensiTest Broth+16 μg/mL 2,2′-bipyridyl). In all casesthe final concentration of DMSO incubated with the bacteria is less thanor equal to 1%. For estimation of the minimal inhibitory concentrations(MIC), 2-fold dilutions of compounds are added to wells of a microtitreplate containing 10⁶ bacteria/mL. Plates are incubated overnight at anappropriate temperature (30° C. or 37° C.) and optical densitiesassessed by eye. The MIC value is defined as the lowest compoundconcentration completely inhibiting visible growth of the test organism.Synergism tests are performed under the same conditions as describedabove but with two antimicrobial agents dispensed in checkerboard format[Isenberg HD (1992) Synergism testing: Broth microdilution checkerboardand broth macrodilution methods. In: Clinical Microbiology ProceduresManual vol. 1. Washington, D.C.: American Society for Microbiology.Sections 5.18.1 to 5.18.28.]. The strains used are: Pseudomonasaeruginosa 6067 (Accession number at the DSMZDeutsche Sammlung vonMikroorganismen and Zellkulturen GmbH, Inhoffenstr. 7 B, D-38124Braunschweig: DSM 18987), Pseudomonas aeruginosa (67/2B)₂R.A. (DSM18988), Achromobacter (formerly Alcaligenes) xylosoxidans QK3/96 (DSM18991), Enterobacter aerogenes Zayakosky 5 (DSM 18992).

Aztreonam as well as compound A and compound B, the latter bothdisclosed in WO 98/47895, which are structurally similar to the compoundof formula I are used as comparators.

Table 1 shows that combining of equal weights of the monobactamantibiotic of formula (I) according to the present invention andcarbapenems of formula II lowers the MIC of the carbapenem againstcarbapenem-resistant strains by an amount that is more than expectedfrom the combination of two active compounds. The MIC of thecombinations according to the invention is also less than the MIC of asimilar equigravimetric combination of aztreonam and the correspondingcarbapenems. Finally, it is shown that the combinations of the presentinvention exhibit lower MIC values than combinations according to WO98/47895, e.g. WO 98/47895, Example 1, which corresponds to Compound Areferred to in Table 1.

TABLE 1 Minimum Inhibitory Concentrations (mg/L) of representativeCombinations between Monobactam Antibiotics and Carbapenems MinimumInhibitory Concentration (mg/L) P. aeruginosa A. xylosoxidans E.aerogenes P. aeruginosa 6067 QK3/96 Zayakosky 5 (67/2B)2R.A.Substance/combination [DSM 18987] [DSM 18991] [DSM 18992] [DSM 18988]Compound of formula I* 16 16 16 32 Aztreonam 16 >64 64 4 CompoundA >64 >64 >64 >64 Compound B >64 >64 >64 >64 Meropenem 16 16 16 4Meropenem + Compound of formula I* 4 8 8 2 Meropenem + aztreonam 16 1616 8 Meropenem + Compound A 16 16 16 8 Meropenem + Compound B 16 16 16 8Imipenem 4 4 32 16 Imipenem + Compound of formula I* 2 4 16 8 Imipenem +aztreonam 4 32 32 16 Imipenem + Compound A 4 32 32 16 Imipenem +Compound B 4 32 32 16 Ertapenem >32 >32 >32 >32 Ertapenem + Compound offormula I* 16 8 16 8 Doripenem 16 16 8 4 Doripenem + Compound of formulaI* 8 8 4 4 *of present application

Fractional inhibitory concentrations (FIC) are determined according tothe formula:

${FIC} = {\frac{{MIC}\mspace{14mu} {of}\mspace{14mu} {drug}\mspace{14mu} A\mspace{14mu} {in}\mspace{14mu} {combination}}{{MIC}\mspace{14mu} {of}\mspace{14mu} {drug}\mspace{14mu} A\mspace{14mu} {alone}} + \frac{{MIC}\mspace{14mu} {of}\mspace{14mu} {drug}\mspace{14mu} B\mspace{14mu} {in}\mspace{14mu} {combination}}{{MIC}\mspace{14mu} {of}\mspace{14mu} {drug}\mspace{14mu} B\mspace{14mu} {alone}}}$

[Isenberg HD (1992); Eliopoulos, G. M. & Moellering, R. C. (1996). InAntibiotics in Laboratory Medicine, 4th edn, (Lorian, V., Ed.), pp.330-96. Williams and Wilkins, Baltimore, Md.].

Table 2 shows the interaction between compound of formula I, or thereference compounds Aztreonam, compound A and compound B, andcarbapenems using the checkerboard titration method. Additive orsynergistic interactions are only observed between the compound offormula I and carbapenem antibiotics. Under the same conditions,combinations with Aztreonam, compound A or compound B show indifferenceor even antagonism.

The interpretation of the FIC values is according to the definitionsgiven by Sader H S, Huynh H K, Jones R N; Contemporary in vitro synergyrates for aztreonam combined with newer fluoroquinolones and β-lactamstested against Gram-negative bacilli; Diagn. Microbiol. Infect. Dis. 47(2003) 547-550, namely as follows:

S=FIC≦0.5: synergism

s=0.5<FIC<1: partial synergism

D=FIC=1: additive effect

I=1<FIC<4: indifferent

N=4≦FIC: antagonism

TABLE 2 Fractional Inhibitory Concentrations (FIC)Observed forRepresentative Combinations between Monobactam Antibiotics andCarbapenems Fractional inhibitory Concentrations A. xylosoxidans E.aerogenes P. aeruginosa P. aeruginosa Substance/combination QK3/96Zayakosky 5 (67/2B)2R.A. 6067 Meropenem + Compound of formula I  0.51 0.48  0.62  0.72 (s) (S) (s) (s) Meropenem + Aztreonam 1.8 1.3 1.1 1.1(I) (I) (I) (I) Meropenem + Compound A 2.1 1.8 3.3 2.2 (I) (I) (I) (I)Meropenem + Compound B 2.0 1.7 3.3 3.3 (I) (I) (I) (I) Imipenem +Compound of formula I  0.78  0.69 1.0  0.62 (s) (s) (D) (s) Imipenem +Aztreonam 9.0 2.1 1.8 2.2 (N) (I) (I) (I) Imipenem + Compound A 5.8 2.42.8 14   (N) (I) (I) (N) Imipenem + Compound B 9.9 2.6 2.7 13   (N) (I)(I) (N) Ertapenem + Compound of formula I 0.7  0.85  0.65 2.0 (s) (s)(s) (I) Doripenem + Compound of formula I  0.37  0.43 1.2 1.0 (S) (S)(I) (D) Doripenem + Compound A 3.1 3.1 7.3 2.4 (I) (I) (N) (I)Doripenem + Compound B 2.3 1.9 4.6 2.4 (I) (I) (N) (I)

We claim:
 1. A pharmaceutical product comprising a monobactam antibiotichaving the oxyimino moiety >C═N—O—, said antibiotic having the formula(I)

wherein the oxyimino moiety has the Z-orientation, or a pharmaceuticallyacceptable salt thereof and at least one carbapenem antibiotic, or apharmaceutically acceptable salt thereof.
 2. The pharmaceutical productof claim 1, comprising at least_one dosage unit comprising the compoundof formula (I) or a pharmaceutically acceptable salt thereof and atleast one dosage unit comprising a carbapenem antibiotic or apharmaceutically acceptable salt thereof.
 3. The pharmaceutical productof claim 1, comprising at least_one dosage unit, each of said dosageunits comprising both, a monobactam antibiotic of formula (I)

or a pharmaceutically acceptable salt thereof and a carbapenemantibiotic or a pharmaceutically acceptable salt thereof.
 4. Thepharmaceutical product of claim 2, wherein the carbapenem antibiotic isselected from the group consisting of the following compounds:

Panipenem and its pharmaceutically acceptable salts in combination withBetamipron and Biapenem, or a pharmaceutically acceptable salt thereof.5. The pharmaceutical product of claim 2, wherein the carbapenemantibiotic is Imipenem or a pharmaceutically acceptable salt thereof, incombination with Cilastin.
 6. The pharmaceutical product of claim 2,wherein the carbapenem antibiotic is Meropenem or a pharmaceuticallyacceptable salt thereof.
 7. The pharmaceutical product of claim 2,wherein the carbapenem antibiotic is Ertapenem or a pharmaceuticallyacceptable salt thereof.
 8. The pharmaceutical product of claim 2,wherein the carbapenem antibiotic is Doripenem or a pharmaceuticallyacceptable salt thereof.
 9. The pharmaceutical product of claim 1,comprising the monobactam antibiotic of formula (I) or thepharmaceutically acceptable salt thereof and the carbapenem antibioticor the pharmaceutically acceptable salt thereof in a weight ratio of10:1 to 1:10.
 10. The pharmaceutical product of claim 9, wherein theweight ratio of the monobactam antibiotic of formula (I) or thepharmaceutically acceptable salt thereof and the carbapenem antibioticor the pharmaceutically acceptable salt thereof is from 3:1 to 1:3. 11.The pharmaceutical product of claim 1, which is a composition comprisingthe monobactam antibiotic of formula (I) or the pharmaceuticallyacceptable salt thereof and a carbapenem antibiotic or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 12. The pharmaceutical product of claim 1 for thetreatment of nosocomial pneumonia, community-acquired pneumonia, urinarytract infection, complicated intra-abdominal infection, complicatedskin/skin structure infection, infectious exacerbations of cysticfibrosis, sepsis, melioidosis.
 13. The pharmaceutical product of claim 1wherein said combination contains one carbapenem antibiotic, or itspharmaceutically acceptable salt.
 14. The pharmaceutical product ofclaim 9 wherein the weight ratio of monobactam antibiotic or its salt tothe carbapenem antibiotic and its salt is 5:1 to 1:5.
 15. Thepharmaceutical product of claim 9 wherein the weight ratio of monobactamantibiotic or its salt to the carbapenem antibiotic and its salt is from2:1 to 1:2.
 16. The pharmaceutical product of claim 9 wherein saidweight ratio is 1:1.
 17. A monobactam antibiotic containing an oxyiminomoiety >C═N—O—, wherein said antibiotic is a compound of formula (I)

wherein the oxyimino moiety has a Z-orientation, or a pharmaceuticallyacceptable salt thereof, said antibiotic being in substantiallycrystalline form.
 18. A packaged kit for treating bacterial infection inmammals comprising at least two dosage units of a pharmaceuticalantibiotic, each dosage unit being in a separate container, one of saidcontainers containing a monobactam antibiotic having an oxyiminomoiety >C═N—O—, said antibiotic having the formula (I)

wherein the oxyimino moiety has the Z-orientation, or a pharmaceuticallyacceptable salt thereof and a second container containing carbapenemantibiotic, or a pharmaceutically acceptable salt thereof.
 19. Thepackaged kit of claim 18, wherein the carbapenem antibiotic is selectedfrom the group consisting of the following compounds:

and Panipenem.
 20. The packaged kit of claim 19 wherein said kitcontains a third container containing the antibiotic Biapenem or itspharmaceutically acceptable salt.
 21. The packaged kit of claim 18wherein the carbapenem antibiotic is Imipenem or a pharmaceuticallyacceptable salt thereof, and said kit contains a third containercontaining the antibiotic Cilastin.
 22. The packaged kit of claim 18wherein the carbapenem antibiotic is Meropenem or a pharmaceuticallyacceptable salt thereof.
 23. The packaged kit of claim 18 wherein thecarbapenem antibiotic is Ertapenem or a pharmaceutically acceptable saltthereof.
 24. The packaged kit of claim 18 wherein the carbapenemantibiotic is Doripenem or a pharmaceutically acceptable salt thereof.